Poly halo-salicylanilioes



United States Patent ice Patented Mar. 1, 1955 011 z z 2.10am: i I t POLY HALO SALICYLANILIDES" X1 -CONHQZ1 Jakob Bindler, Riehen, near Basel, andErnst Model, Basel, 5 g, Y (In Switzerland, assignors to J. R Geigy A. G., Basel, Switzerland, a Swiss firm herei No Drawing Appfigafim Deqgmbier 1952" Q represents hydrogen or halogen,

Sena! 327,670 X represents hydrogen, halogen or the methyl group, Claims priority, application Switzerland 7 Y represents hydrogen, halogen or the trifiuoromethyl v group, an December 1951 Z represents hydrogen or halogen, 6 Claims. (Cl. 260 659) whereby a halogen atom must be present 1n one of the h present in io concerns a ma fmthe positions of the anilide radical not neighbouring the amide duction of bactericidal salicyl'anilidc's which are very suitgroup and 111 One Of the Pairs X'IXZ and 1 0r 2 able as active ingredients in disiflfe'c'tanfs both symbols must represent substituents of the type de- It has been found that suchs'alieylanil-ides which con; e pafhcuhlfly favourable 9 P e those 111 tain two neighbouring halogen substituentsin o e f h t .which also Z1 represents halogen in the substitut on in coutwo benzene rings, of which one must bein' the para-posi- P 9 5 X 1X2 Or e One X represents halogen n the tion to the carbamide bridge and the other ino'ne of the Shluhon in couples 1H YZ'I or Z 122. meta-positions, are characterised by particularly strong In the P P aecorFhhg the Present mY Sultbactericidal properties. The bactericidal activity is moreable acylatlhg deflvatlves 0f ha10geh' suhstltuted over particularly great if the other benzene ring'also con- -dfoiiyhehlelle-l-earboxyhe fields are the fespeehve d tains one or more halogen substituentsga halogen substithalides and the cor I p g Y Y F- F- uent in the para-position to the carbamide bridge is paryh acld m Pa a the correspondmg acld ticularly active. The halogen substituent canalso be in ehlcjrldes come W cohsldemhohy y y the meta-position provided that there are otherhalogen hahde? are used e the PY Y group must finally be substituents, it being of advantage if a secondsubstituent sapohlfied under mlld eohqlhhns E h y y g p in the anilide radical isin the para-position to the first one. example h non-Caustic alkalles 1n aqlleous q 3.5 dihalogen substitution comes into question in the hem -h e 9 In the Process aeeordlhg 0 the P zoyl radical. In the present invention it is often of advanem laventlpn, 15 not necessary to Staff fIOm h altage it the trifluoromethyl group replaces a halogenatom hoxyhe field hahdes themselves" There Is a p y in the dihalogen substitution in couples. Also a methyl advahtageeus methed h Production already lI10W1 1 Which group can take the placg of a. halg'genatonyin thgben'zoyl COIlSlSlLS 1n hCfltlllg SllltflblC Z-hYdl'OXYbCIlZOIC ZlCldS and radical, advantageously in the 4-positionwhen there'is a the ha10geh-ah 11n0be 11ZeI le pompeunde usable aeeerdlng halogen 310 -11 in the S-POSifiOIL active substitution [0 the Plfisfilli. lllVEIlilOIl Ill lllel't organic S'OlV-BlllZS such as in couples can naturally also take place in the two benzene 40 toluene, ,ehlorohehzehe, hltmhenlehe, h t ewith rings, even so not only is further halogen substitution, dehydl'atmg hgems Such as P Q P hlehlollde of particularly in the anilide radical, admissible but often thlohyl ehloflde, Y 1n the Presence of all favourable when in the substitution 'by halogen in couples amounts of h m ehlolldeaccording to the present invention, a third halogen atom follohfmg, z-hydmxyhehzenejl'earbexyhe a s or takes one of the remaining positions. The bactericidal ?Y derlvahves thereof Usable 111 h P s or salicylanilidcs according to the'presentinvention are charmg to the Present lhvelltloh e 9 j 0 mo; acterised, therefore, by substitution of the benzene rings y y eh held, '9-, in couples acording to the following formula: 'dl-lodo'zrhyfhoxybelllehe1teal'hoXyhe acid,

4-methyl-5-chloroor -1odoor -bromm2-hydroxyben- OH zene-l-carboxylic acid, 4.5dichloroor -dibromo-2-hydrtxybebnzene-l-carbgxylic acid. b 7 V uita 1e 4- or 5- alogen-l-amino enzene compounds G are: 4-chloro-, 4-bromoor 4-iodo-aniline, 2.4- or 2.5-di- I chloroor dibromo-aniline, 2.4.S-trichloro-aniline, 3.4-,di- X2 Y1 v (I) chloro-aniline, '3-trifluoromethyl-4-chloro-aniline,' 2.3.4-

. trichloro-aniline and 3.4.5-trichloroaniline are particularly wherein either X1 and X2 represent halogen or Y1 rep suitable components. 4 resents methyl and X2 represents halogen, or Y1 and Y The salicylanilides according to this inventlon are colrepresent halogen or Y1 represents-the trifluoromethyl ourless powders which in aqueous-alkaline solutions of group and Y2 represents halogen. no strong alkalies are easily soluble, even in the cold; They Here and in the following, for technical reasons, prefhave very good bactericidal properties and are suitable, erably chlorine is to be understood by halogen, but also therefore, either as such or mixed with other substances bromine and iodine compounds are active. such as cleaning agents, ointment bases, creams, etc. for The new bactericidal salicylanilides are obtained by rethe disinfection of material treated with such preparaacting acylating derivatives of a Z-hydroxybenzene-l-cartions. boxylic acid which can contain halogen substituents in the The following examples illustrate the invention withpositions not next to the carbonyl group in the benzene out limiting it in any Way. Where not otherwise stated, ring and, if,desired, can have a methyl group in the 4- or parts are given as parts by weight and the temperatures 5-position to the carboxyl group, with a 5-, or preferably are in degrees centigrade. The relationship of parts by a 4-halogen-l-aminobenzene compound which, with adweight to parts-by volume is as that of kilogrammes to vantage, can contain further halogen substituentsor a trilitres. t fluoromethyl group, the latter in the Inga-position. to the EXAMPLE 1 amino roup. If the para-positiontot e amino group is free, a para-dihalogen substitution of the benzene ring is 5 chlomsalwyhc dwhlom amhde necessary to obtain a good action. An ortho-po'sitio'n to 43 parts of S-chlorosahcyhc acid and 40 parts of 3,4- the amino group must be free in the halogen-aminobendichloroaniline are dissolved in 450 parts of chlorobenzene compound used whereas the other can be occupied by zene and 1 part of aluminium chloride and 15 parts of halogen. The components should be so chosenthat the phosphorus trichloride are added. This suspension is salicylanilides obtained, after saponification of anacyloxy boiled until no more hydrogen chloride is generated, which group to the hydroxyl group" it necessary,"eorrespond to go is about for 2-3 hours. The chlorobenzene solution is the general Formula H then mixed with water and made alkaline to brilliant yelaniline is used.

EXAMPLE 2 4.5-dichlr0salicylic acid-3'.4'-dichl0r0-anilide 185 parts of the sodium salt of 3.4-dichlorophcnol are dried in an autoclave for 3 hours at 100-110 under reduced pressure. After cooling to 35-40, CO2 under 8 atmospheres pressure is introduced until the pressure remains constant. The whole is then heated for 6 hours at 150-160". The contents of the autoclave when cooled are taken up in 1000 parts by volume of Water and the 4.5-dichlorosalicylic acid is precipitated with hydrochloric acid. After recrystallisation from diluted alcohol, it melts at 206-207".

21 parts of 4.5-dichlorosalicylic acid are mixed with 50 parts of benzene and 50 parts of acetic acid anhydride. A trace of a mixture of sulphuric acid and glacial acetic acid is added and the whole is heated to 80-90". After cooling, the crystals are filtered oflf under suction and then washed with a little benzene and water and dried. 2-acetoxy-4.S-dichlorobenzoic acid is obtained in the form of white crystals. M. P. 163-165 21.5 parts of 4.5-dichloro-2-acetoxybenzoic acid are stirred with 30 parts of freshly distilled thionyl chloride, 0.1 part of pyridine in 1 part of benzene is added. The whole is stirred at 4550 until the reaction is complete. Finally the whole is diluted with a little benzene and then evaporated to dryness at 50-60 under reduced pressure.

The raw acid chloride which is obtained, a pale yellowish oil, is suspended in 400 parts by volume of chlorobenzene and boiled with 16 parts of 3.4-dichloroaniline in an oil bath until no more hydrogen chloride is generated. The reaction mixture is then poured into water and made alkaline. The solvent is removed with steam at the same time as the acetyl group is saponified. The 4.5-dichlorosalicylic acid-3'.4'-dichloroanilide so obtained is recrystallised from glacial acetic acid. M. P. 25 8259.

EXAMPLE 3 4.5-dichl0rosalicylic acid-2'.4-dichIoro-anilide 21 parts of 4.5-dichlorosalicylic acid and 16 parts of 2.4-dichloro-aniline are dissolved in 400 parts of chloro- EXAMPLE 4 4.5-dichl0rosalicylic acid-2'.3'.4'-trichloro-anilia'e 21 parts of 4.5-dichloro-2-hydroxybenzene-l-carboxylic acid, 0.4 part of anhydrous aluminium chloride and 19.5

parts of 2.3.4-trichloro-aniline are suspended in 400 parts by volume of chlorobenzenc. 6 parts of phosphorus trichloride are added. The mixture is boiled until a clear solution is obtained and until no more hydrogen chloride is generated. The filtered solution is neutralised with soda, the chlorobenzene is removed with steam and the residue is filtered off. The 4.5-dichloro-2-hydroxybenzoyl-2.3.4'-trichloro-anilide melts at 254255 after recrystallisation from ethylene glycol monomethyl ether.

EXAMPLE 5 5-clzlorosnlicylic acid-2.3-4-trichl0ranilide 18 parts of 5-chloro-2-hydroxybenzene-l-carboxylic acid, 19.5 parts of 2.3.4-trich1oro-aniline, 0.4 part of aluminium chloride and 6 parts of phosphorus trichloride are suspended in 400 parts by volume of chlorobenzenc and boiled until a clear solution is obtained. The solution is filtered hot, neutralised with soda and the solvent is removed with steam. The 5-chloro-2-hydroxybenzoyl- 2'.3'.4'-trichloro-anilide, recrystallised from ethylene glycol monomethyl ether, melts at 248-249.

If, instead of 5-chloro-2-hydroxybenzene-l-carboxylic acid, the corresponding S-bromine compound is used and the reaction product is recrystallised from butyl alcohol, 5-brom0-2-hydroxy-benzoyl-2'.3'.4' trichloro anilide is obtained which melts at 245-246.

EXAMPLE 6 3.5-dichlorosalicylic acid-2'.3'.4-tricliloro-anilide 21 parts of 3.5-dichloro-2-hydroxybenzene-l-carboxylic acid, 0.4 part of aluminium chloride and 6 parts of phosphorus trichloride are added to a solution of 19.5 parts of 2.3.4-trichloroaniline in 400 parts of chlorobenzenc. The suspension so obtained is boiled until no more hydrogen chloride is generated. Slight amounts of undissolved substances are filtered off from the solution, the filtrate is neutralised with soda solution and the chlorobenzene is removed with steam. After filtering and recrystallisation from ethylene glycol monomethyl ether, 3.5-dichloro-2-hydroxybenzoyl-2.3'.4'-trichloro-anilide is obtained which melts at 224-225.

The salicylanilides given in the following table are prepared in a manner analogous to those described in the examples. Their bactericidal properties are determined on Staphylowccusam'eus as follows:

A standard suspension, which is prepared by adding sterilised tap water to the germs of 16 hour agar cultures, the density of which is brought to transparency in the so-called I-Iellige Bio-Photo-Col apparatus, is mixed with graduated dilutions .of the disinfectant to be tested (in aqueous solution). Duration of test: 10 minutes, temperature: 20.

At the end of the 10 minutes, 2 sub-cultures from each reaction mixture are preparedwith a glucose broth. The sub-cultures are bred at 37 C. After 48 hours, the development or sterility of the sub-cultures is determined. The bactericidal activity of a disinfectant is determined by the minimal concentration required to kill, with certainty, a standard suspension of test germs under certain conditions. The minimal concentration having a bactericidal action is ascertained by graduated concentrations according to the dilution process principle and is expressed in 10' mol.

TABLE Minimal active M P bactericidal N0. Halogeuated salicylic acid Halogenated amline concentra- (degrees) on pressed in 10 mo].

1 5-chlorosalicylic acid 3,4-dichloroaniline 246-248 I). 25 2 d0 3-trlfiuoromethyl-4cl1loro-aniline 229-230 6. 25

3.4.5-trlchloro-aniline 283-284 t. 1 2.4.5-trtchloro-aniliue. 219-221 0. G 3.4dichlor0-aniline 321-222 1 2. 5 3.4.5-trichloro-an1ltnc 261-262 5.1 2.4.5-trichloro-aniline 251-252 I I. 1 3- LfluoromethyH-ehloro-aniline 183-184 11. 5 2.4.5-trichloro-aniline... 185-186 10 3.4.5-trichloro-aniline... 185 5.1 B-trifluoromethyl 4 chlo 134-135 12. 5 3.4-dlchloro-an1l1ne--. 198-199 6. 6 3.4.5-trichloro-anlline 222-223 3. 0

TABLE-Continued Minimal active M P bactericidal No. Halogenated salicylic acid Halogenated aniline concentra- (degrees) tlon expressed in 14 4.5-d1chloro-salicylic acid 3. 1 15 d 12. 5 1 6 d n 3. 1 17 4.5-dichloro-salieylic acid 6. 25 18 4-methyl-5-chloro-salicylic acid- 6 19 d 3. 0 20 d n 3. 0 21 fi-bromo-salicylic acid 6. 2 22 do 3.4.5-trichloro-anillne 3. 1 23 4.5-dichloro-salicylic acid 2.4-dichloro-auiltne 6. 6 24 o 2.5-dlehloro-anlline 222-223 6. 6 25 do 4-ch10lo-nnilinn 258-259 3- 1 26 do 2.4-dibromo-aniline..- 229-230 3. 1 27 o t-bromo-aniline. 257-258 6. 2 28 do 2.3.4-trlchloro-anlline- 254-255 3. 1 29 B-chloro-salieylie aci do 248-249 3. 1 30 salicylic acid 3.4.5-triehloro-aniline 257-258 12. 5

EXAMPLE 7 100 parts of dyed or undyed cotton are impregnated with a solution obtained by dissolving 2-5 parts of a salicylanilide obtained according to Example 1 in 50 parts by volume of ethyl alcohol with the aid of a few drops of caustic soda lye 30% and then diluting the clear solution with water up to 1000 parts. The cotton is left in the solution for 15-30 minutes at 30-50 whereupon it is wrung out and dried.

The cellulose fibres so treated have an increased resistance to mould and against rot caused by micro-organ- 151118.

What we claim is:

1. A polyhalogen-substituted salicylanilide containing at least three halogenous substituents in the X-positions, of the general formula:

Q 011 Y XPQMHQX. 2 0

wherein Q represents a member selected from the group consisting of hydrogen, chlorine, bromine and iodine, X1 and X2 each represent a member selected from the group consisting of hydrogen, chlorine, bromine, iodine and CH3, X represents a member selected from the group consisting of hydrogen, chlorine, bromine and CE, and X4 and Y each represent a member selected from the group consisting of hydrogen, chlorine and bromine.

2. A salicylanilide of the formula:

(IO-NHQOI 1 1 3. A salicylanilide of the formula:

OH O] 25 4. A salicylanilide of the formula:

0H e1- QQ-NHQQ] 30 1 F:

5. A salicylanilide of the formula:

0H 01 c1 CO-NHQ 4o 6. A salicylanilide of the formula:

OH 01 Cl Hirwe et al., J. Indian Chem. Soc., vol. 16 (1939), pp. 281-284.

2Aglltan et al., Organic Synthesis, vol. 26 (1946), pp.

Anschutz et al., Liebigs Annalen," vol. 346 (1906). pp. 305, 314, 326 and 332. 

1. A POLYHALOGEN-SUBSTITUTED SALICYLANILIDE CONTAINING AT LEAST THREE HALOGENOUS SUBSTITUENTS IN THE X-POSITIONS, OF THE GENERAL FORMULA: 